Alpha-para-hydroxyphenyl-beta-methylaminopropanol and process of preparing it



Patented Sept. 20, 1932 UNITED STATES Farsi, F ues FRIEDRICH STOLZ, OF FRANKFORT-ON-THE-MAIN-HOGHST, GERMANY, ASSIGNOR TO WINTHROP CHEMICAL COMPANY, INC., OF NEW YORK, N. Y., A CORPORATION OF NEW YORK a-PARA-HYDROXYPHENYL-fl METHYLAMINOPROIPANOL AND PROCESS OF PREPARING IT No Drawing. Application filed June 21, 1929, Seria1 No. 372,798, and in Germany June 27, 1928.

which is important owing to its valuable therapeutic properties, can be prepared by hydrogenating a compound of the following formula:

N 7 p I 0H: no-O-o-oH-om wherein X stands for hydrogen or the group GH C H The para-hydroxymethylaminopropiophenone can, for instance, be obtained by causing methylamine to act upon para-acetoxybromopropiophenone and in the same manner parahydroxymethyl benzylaminopropiophenone is obtained by the action of. methylbenzylamine. The para-acetoXybrom-propiophenone is preferably obtained by brominating para,- acetoXy-propiophenone in glacial acetic acid, chloroform or another suitable solvent.

I have furthermore found that a-para-hy droxyphenyl ,8 metliylaminopropanol can also be prepared'by diazotiring para-aminophenyl-methylaminopropanol and heating the solution so obtained with or without addition of copper or another metal or a salt thereof.

Para aminophenyl methylaminoprop anol can, for instance,be obtained from para-ace tylamino a methylaminopropiophenone by first reducing it catalytically and then saponifying the reduced compound or first saponifying it and then reducing the saponified compound.

Para acetylamino -{oz -=methylaminopropiophenone can be obtained by causing monomethylamine in an aqueous alcoholic solution to act upon a-brompropionyl-acetanilide (prepared from acetanilide and a-brompropionylohloride by means of aluminum chloride). The solvent is distilled off in vacuo formula OH N 3 HoOli-tH-om are dissolved in 1000 parts of normal hydrochloric acid. After addition of a' nickel catalyst, the whole is hydrogenated for one hour at 100 C. and under a pressure ofhydrogen of 4.0 atmospheres. After cooling, the solution which has been separated from the toluene split off and from the catalyst is acidified, and shaken out several times with ether, in order'to remove the non-basic parts, then the whole is neutralized and some dissolved iron and nickel is precipitated with the required quantity of ammonium sulfide. To the filtrate is added a sufficiently con centrated potassium carbonate solution, whereupon, when rubbing with a glass rod, the new base precipitates in the form of a crystalline powder. After standing, for some time in ice itis filtered by suction and washed with cold water. From the filtrate there can also be obtained an isomeric base.

The para-hydroxyphenylmethylaminopropanol thus prepared forms a white crystalline powder, melting at 152 (1 154 C. It is difficulty soluble in water, alcohol and ether and is readily soluble in caustic soda solution and diluted acids. The hydrochloride melts at 209 C.211 (1; and is readily soluble in water with a neutral reaction.

Instead of by means of nickel catalysts, the hydrogenation can also be carried out with palladium at ordinary temperature' Instead of 269 parts of para-hydroxymethylbenzylaminopropiophenone, 179 parts of para-hydroXymethylaminopropiophenone nnvO-onon-onqarn are dissolved with 9 parts of sulfuricacid of 20% strength in 36 parts of water, the

solution is cooled with ice and diazotized by the addition of 10 parts by volume of normal nitrite solution. Then some copper powder is added thereto and the whole is heated on thevapor bath until the evolution of. nitrogen which soon takes place, is finished and a test sample no longer couples with B- naphtholdisu lfonic acid. By means of an excess of caustic soda solution, dissolved copper precipitated, which is filtered 0E. The filtrate is neutralized with carbonic acid or a mineral acid and then the parahydroxyphenylmethylaminopropanol is precipitated in the form of a white crystalline powder by addition of ample potassium carbonate. It is difiicul-tly soluble in water, alcohol and ether and melts at 152 i=1 154 0; By neutralization with alcoholic hydrochloric acid the hydrochloride is obtained being readily soluble in water with a neutral reaction and diificultlysoluble in alcohol; it melts at 209 O.211 G. The oxalate is readily soluble in hot water and crystallizes when slowly cooled in fine crystals, melting at 216 C.218 C. The base is. readily soluble in diluted caustic soda solution.

28 parts of para-aminophenyl methylaminopropanolsulfate are dissolvedin 250 parts of'water, 50 parts of sulfuric acid of 20% strength are added thereto and the mixture is diazotized by means of 100 parts by volume of normal nitrite solution. Then the whole is gently heated on the steam bath until a test sample no longer couples with Banaphtholdisulfonic acid. When the liquid no longer couples with ,Q-naphtholdisulfonic acid; even on a further addition of nitrite, the. reaction is finished. Then the whole is filtered, the filtrate is supersaturated with a. potassium carbonate solution and the resulting para-hydroxyphenyl-methylaminopropanol is shaken out with acetic ester. The base remaining after distillation of. the acetic ester is neutralized with alcoholic hydrochloric acid and the resulting hydrochloride is recrystallized from alcohol; it melts at 209 C.21-1 C.

(4.) ldparts of the sulfate ofgpara aminophenyl-methyleaminopropanol are dissolved inleO pa nts of water, 30 parts of sulfuric acid of 20% strength are added thereto, the mixture is cooled with ice and diazotized by means of 50 parts by volume of a normal nitrite solution. After the addition. of a mall qu i y r ced n k l, he whole 1s heated on the steam bath until the evolution of nitrogen is finished and a test sample no longer coupleswith fl-naphtholdisulfonic acid. WVhenadiazotizablebase isno longer present, the whole is filtered, caustic soda solution is added until there. is, a neutral reaction to, Congo paper and any dissolved nickel is precipitated by cautiously adding a sodium ulfide sel i iqe. T e prs pite aoi, ni sulfide is filtered, the filtrate is'supersaturated with a potassium carbonate solution and the para-hydroXyphenyl-methylaminopro panol is shakenout with acetic ester. The hydrochloride preparedtherefrom melts at 209 C.211 (3.; it is. readily soluble. in water with a neutral reaction. I

(5.) 90 parts of paraaaminophenyl-methylam nopr pa ol a e di olved g th w th 45 par s o l r aci 20% str ng h il 00. part of; W t r. and. hi e o i g W th. ice, diazotized by means of 500 parts-by vol: ume of a normal nitrite solution. Then a solution of 5 parts of cobaltous-chloride is added thereto and the whole. is gradually heated on the vapor-bath until no more nitrogen escapes and a test sample does no longer couple with B-naphtholdisulfonic v acid. When the reaction iscompletethe. liquid is neutralized with caustic soda solution until Congo paper-isno, longer-blued and then the cobalt isprecipitated-by the'just required quantity of a sodium sulfide solution. Then the mass is filtered, rendered alkaline by means of ammonia and the: para-hydroxyphenylnnethylaminoprop anol is shaken out with aceticester-by means of-ammonium-suL fate. Thebase remaining after the distillationofthe solvent is purifiedby-transforming it intothe hydrochloride. i

I claim: 1. The processwhich consists in hydrogenating a compound of the following formula: ont oum" V N 3.- BOO-d-OH-OH: 1

dissolved in,therequiredquantity of normal hydrochloric acid, in thepresenc'e' of a nickel catalyst for one hour at, 100 andunder a pressure of hydrogen of 40' atmospheres.

2. Asa new product," the compound of the following formula: V

on. Ni -.0113

I noOtracn-ome g a h te y a ine, pow er, m ng a 152 Cit-154 0., being. difficultly soluble in water, alcohol. and; ethemreadily. soluble in cau t d mme-m1. ilu eth hydrochloride melting at 209 (1-211 C. and being readily soluble with a neutral reaction.-

3. The process which consists in hydrogenating a salt of a base of the following general formula:

X 0 IT O H:

i wherein X stands for hydrogen or the group CH .C H in an aqueous solution and in the presence of a hydrogenation catalyst.

In testimony whereof, I affix my signature.

l FRIEDRICH STOLZ. 

